Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents
Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (<b>1</b>–<b>6</b>) that are mono-substituted in the axial position with a non-...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/9/2460 |
| _version_ | 1797602914036875264 |
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| author | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright |
| author_facet | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright |
| author_sort | Angelico D. Aputen |
| collection | DOAJ |
| description | Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (<b>1</b>–<b>6</b>) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of <b>1</b>–<b>6</b>. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (<b>5</b> and <b>6</b>) were determined to be the most biologically potent, demonstrating GI<sub>50</sub> values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, <b>6</b> elicited a GI<sub>50</sub> value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for <b>1</b>–<b>6</b> in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy. |
| first_indexed | 2024-03-11T04:23:15Z |
| format | Article |
| id | doaj.art-6c48a9c548194143a2c0eac05a7a30cf |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T04:23:15Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6c48a9c548194143a2c0eac05a7a30cf2023-11-17T22:40:08ZengMDPI AGCancers2072-66942023-04-01159246010.3390/cancers15092460Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory AgentsAngelico D. Aputen0Maria George Elias1Jayne Gilbert2Jennette A. Sakoff3Christopher P. Gordon4Kieran F. Scott5Janice R. Aldrich-Wright6School of Science, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, AustraliaCalvary Mater Newcastle Hospital, Waratah, Newcastle, NSW 2298, AustraliaCalvary Mater Newcastle Hospital, Waratah, Newcastle, NSW 2298, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, AustraliaIngham Institute, Liverpool, Sydney, NSW 2170, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, AustraliaDeveloping new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (<b>1</b>–<b>6</b>) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of <b>1</b>–<b>6</b>. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (<b>5</b> and <b>6</b>) were determined to be the most biologically potent, demonstrating GI<sub>50</sub> values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, <b>6</b> elicited a GI<sub>50</sub> value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for <b>1</b>–<b>6</b> in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.https://www.mdpi.com/2072-6694/15/9/2460platinum(II)cisplatinchemotherapyplatinum(IV)naproxenacemetacin |
| spellingShingle | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents Cancers platinum(II) cisplatin chemotherapy platinum(IV) naproxen acemetacin |
| title | Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents |
| title_full | Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents |
| title_fullStr | Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents |
| title_full_unstemmed | Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents |
| title_short | Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents |
| title_sort | versatile platinum iv prodrugs of naproxen and acemetacin as chemo anti inflammatory agents |
| topic | platinum(II) cisplatin chemotherapy platinum(IV) naproxen acemetacin |
| url | https://www.mdpi.com/2072-6694/15/9/2460 |
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